The synthesis of monoclonal immunoglobulins displaying cryoglobulin behavior is associated with several different lymphoproliferative disorders. Depending on the absolute concentration, specific immunoglobulin class and relative cold sensitivity of these proteins, a range of cutaneous, neurologic, renal and vasomotor complications can develop. The studies proposed in this application are directed at elucidating the molecular basis for cryoglobulin properties associated with some monoclonal IgM, kappa immunoglobulins. The structural requirements for cryoprecipitation will be examined by estimating the capacity of chemically and enzymatically derived fragments to either cryoprecipitate or influence cryoprecipitation of the intact molecule. Systematic investigation of the effects of various solutes on cryoprecipitation will be utilized to evaluate intermolecular forces involved with formation and stabilization of the cryoprecipitate, compare the various forces involved in precipitation of different cryoglobulins and relate cryoprecipitation to other forms of thermodynamically reversible macromolecular association. Techniques such as circular dichroism spectroscopy, Laser-Raman spectroscopy, analysis of hydrogen exchange kinetics and hydrophobic chromatography will be used to measure various parameters of cryoglobulin conformation as a function of temperature. The relationship of primary structure to cryoprecipitation will be sought through comparative amino acid composition analysis, amino acid sequencing and chemical modification of IgM, kappa cryoglobulins and other IgM, kappa immunoglobulins lacking cryoglobulin behavior. In these studies, the relative contributions of a specific intermolecular recognition process vs. an overall molecular solubility phenomenon toward the cold-induced precipitation will be examined.